In the JournalsPerspective

Lp(a) reduction goals may have been overestimated in previous trials

George Thanassoulis
George Thanassoulis

Reducing lipoprotein(a) by 65.7 mg/dL may have the same effect on clinical outcomes as a reduction in LDL to 38.67 mg/dL, according to a Mendelian randomization analysis published in JAMA Cardiology.

Claudia Lamina, PhD, of the division of genetic epidemiology at the Medical University of Innsbruck in Austria and of the division of genetic epidemiology at the Institute for Medical Biometry and Statistics at University of Freiburg in Germany, and Florian Kronenberg, MD, professor at the Medical University of Innsbruck, and colleagues analyzed data from 13,781 patients from the Lp(a)-GWAS-Consortium from five studies, 20,793 cases of CHD and 27,540 controls.

The mean age of the patients in four of the five studies was 51 to 59 years; the mean age of patients from the fifth study was 32 years. The studies comprised between 51% and 55% women.

Lp(a) concentrations were measured at the same laboratory and ranged from 11 mg/dL to 12 mg/dL. The data set also included 27 single nucleotide polymorphisms on Lp(a).

A reduction in Lp(a) by 65.7 mg/dL (95% CI, 46.3-88.3) would result in a 45% lifetime risk reduction for CHD and a 22% reduction in short-term risk, according to the researchers.

“These results have important implications for the planning of randomized clinical trials of drugs that target Lp(a) concentrations,” the researchers wrote. “First, these drugs need to have a pronounced Lp(a) lowering potential, which we estimated to be 65.7 mg/dL, but more than 100 mg/dL might be an overestimate. ... Second, the upcoming first trials should include patients with Lp(a) greater than 100 mg/dL at baseline to achieve an Lp(a) concentration less than 30 mg/dL by treatment. Third, the Lp(a) assay used for identification of patients for treatment have to be well-standardized to avoid an overestimation or underestimation of Lp(a) concentrations and thereby an inappropriate recruitment of patients.”

Reducing lipoprotein(a) by 65.7 mg/dL may have the same effect on clinical outcomes as a reduction in LDL to 38.67 mg/dL, according to a Mendelian randomization analysis published in JAMA Cardiology.
Source: Adobe Stock

“Notwithstanding these limitations, it is nonetheless remarkable that we can validate novel therapeutic targets such as Lp(a) and also resolve key trial parameters prior to starting any [randomized controlled trial], based on such genetic studies,” George Thanassoulis, MD, MSc, FRCPC, director of preventive and genomic cardiology at McGill University Health Centre in Montreal and assistant professor of medicine at McGill University, wrote in a related editorial. “Mendelian randomization has been instrumental in the resurgence of Lp(a) in the cardiovascular community, arguably more so than for any other biomarker. Indeed, much of the current understanding of Lp(a) has been derived from such studies.” – by Darlene Dobkowski

Disclosures: Lamina reports no relevant financial disclosures. Kronenberg reports he received personal fees from Amgen and Kaneka. Thanassoulis reports he participated in advisory boards for Amgen, Ionis and Sanofi-Regeneron; participated in speaker bureaus for Amgen and Sanofi, and received grant funding from Ionis and Servier.

 

George Thanassoulis
George Thanassoulis

Reducing lipoprotein(a) by 65.7 mg/dL may have the same effect on clinical outcomes as a reduction in LDL to 38.67 mg/dL, according to a Mendelian randomization analysis published in JAMA Cardiology.

Claudia Lamina, PhD, of the division of genetic epidemiology at the Medical University of Innsbruck in Austria and of the division of genetic epidemiology at the Institute for Medical Biometry and Statistics at University of Freiburg in Germany, and Florian Kronenberg, MD, professor at the Medical University of Innsbruck, and colleagues analyzed data from 13,781 patients from the Lp(a)-GWAS-Consortium from five studies, 20,793 cases of CHD and 27,540 controls.

The mean age of the patients in four of the five studies was 51 to 59 years; the mean age of patients from the fifth study was 32 years. The studies comprised between 51% and 55% women.

Lp(a) concentrations were measured at the same laboratory and ranged from 11 mg/dL to 12 mg/dL. The data set also included 27 single nucleotide polymorphisms on Lp(a).

A reduction in Lp(a) by 65.7 mg/dL (95% CI, 46.3-88.3) would result in a 45% lifetime risk reduction for CHD and a 22% reduction in short-term risk, according to the researchers.

“These results have important implications for the planning of randomized clinical trials of drugs that target Lp(a) concentrations,” the researchers wrote. “First, these drugs need to have a pronounced Lp(a) lowering potential, which we estimated to be 65.7 mg/dL, but more than 100 mg/dL might be an overestimate. ... Second, the upcoming first trials should include patients with Lp(a) greater than 100 mg/dL at baseline to achieve an Lp(a) concentration less than 30 mg/dL by treatment. Third, the Lp(a) assay used for identification of patients for treatment have to be well-standardized to avoid an overestimation or underestimation of Lp(a) concentrations and thereby an inappropriate recruitment of patients.”

Reducing lipoprotein(a) by 65.7 mg/dL may have the same effect on clinical outcomes as a reduction in LDL to 38.67 mg/dL, according to a Mendelian randomization analysis published in JAMA Cardiology.
Source: Adobe Stock

“Notwithstanding these limitations, it is nonetheless remarkable that we can validate novel therapeutic targets such as Lp(a) and also resolve key trial parameters prior to starting any [randomized controlled trial], based on such genetic studies,” George Thanassoulis, MD, MSc, FRCPC, director of preventive and genomic cardiology at McGill University Health Centre in Montreal and assistant professor of medicine at McGill University, wrote in a related editorial. “Mendelian randomization has been instrumental in the resurgence of Lp(a) in the cardiovascular community, arguably more so than for any other biomarker. Indeed, much of the current understanding of Lp(a) has been derived from such studies.” – by Darlene Dobkowski

Disclosures: Lamina reports no relevant financial disclosures. Kronenberg reports he received personal fees from Amgen and Kaneka. Thanassoulis reports he participated in advisory boards for Amgen, Ionis and Sanofi-Regeneron; participated in speaker bureaus for Amgen and Sanofi, and received grant funding from Ionis and Servier.

 

    Perspective
    Joshua W. Knowles

    Joshua W. Knowles

    For several years now, we have known that Lp(a) is a causal risk factor for CVD. That is still relatively new and not everybody probably appreciates that yet, but it is certainly a risk factor. We have not known exactly how potent a risk factor it is, although it is clearly less potent on a molecule-per-molecule basis than LDL cholesterol particles. That has been a bit of a debate because how potent a risk factor Lp(a) is has major implications on how much it must be lowered to get a therapeutic effect which will also affect clinical trial design.

    Analyses published last year by a very good group suggested that on a per-molecule basis, Lp(a) was a three or four times weaker risk factor than LDL cholesterol particles. What that essentially means is that to get a reasonable decrease in events would require therapies that would lower Lp(a) by 80% or more in patients with high Lp(a) levels. To lower Lp(a) by 80% is not easy.

    There are some antisense molecules that are in clinical trials now that do it, but existing therapies like niacin and PCSK9 inhibitors do not lower Lp(a) by nearly that much. There has been interest in trying to figure out this question.

    What this study showed is that you might not have to lower it quite that much to get a dramatic effect on reducing CV outcomes. Reduction by 60 mg/dL or 70 mg/dL may suffice rather than 80 mg/dL, 90 mg/dL or 100 mg/dL. It might make therapies for Lp(a) a little bit more attractive.

    I do not know that these findings have implications for clinical practice right at the moment because we are still waiting on those Lp(a)-lowering therapies. The magnitude of Lp(a) drop that you get from PCSK9 inhibitors is still not this large as what researchers forecasted. There might be a marginal benefit for PCSK9 inhibitors for patients with very high Lp(a), but that effect is not mostly because of the Lp(a)-lowering property.

    As of today, these findings mostly have implications for clinical trial design and drug therapies that might be coming in the future.

    Lp(a) is a bit of a mystery, so there are some fundamental knowledge gaps of Lp(a). One is why do we have Lp(a)? There is definitely research needed in that area.

    How is Lp(a) cleared and metabolized? We still have not identified a canonical receptor for Lp(a) clearance. We have the receptor for LDL particles, but we do not know how Lp(a) is cleared. That is a fundamental question that may have major implications if that mechanism can be identified. Clinical trials are needed to demonstrate efficacy.

    • Joshua W. Knowles, MD, PhD
    • Cardiology Today Next Gen Innovator
      Assistant Professor of Medicine
      Stanford University Medical Center

    Disclosures: Knowles reports his institution was a site for and he was a co-investigator on a Lp(a)-lowering antisense trial sponsored by Akcea.

    Perspective
    David J. Maron

    David J. Maron

    If the conclusions are correct, a given amount of Lp(a) reduction will result in greater risk reduction than previously thought.

    If the powerful antisense oligonucleotide under development is approved, it may result in even greater reduction in risk than we imagined.

    We need a definitive randomized controlled clinical outcomes trial to prove the magnitude of benefit from lowering Lp(a).

    While we wait for definitive evidence regarding the efficacy of Lp(a) lowering to reduce risk, don’t forget that LDL is a more potent risk factor for coronary disease than Lp(a), and we have drugs available that are very effective in lowering LDL that have been shown to lower risk.

    • David J. Maron, MD
    • Director of Preventive Cardiology
      Clinical Professor of Medicine
      Stanford University School of Medicine

    Disclosures: Maron reports no relevant financial disclosures.